Copper accumulation and the effect of chelation treatment on cerebral amyloid angiopathy compared to parenchymal amyloid plaques.
Copper accumulation and the effect of chelation treatment on cerebral amyloid angiopathy compared to parenchymal amyloid plaques.
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DOI：
10.1039/c9mt00306a
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发表时间：
2020-04-01
期刊：
影响因子：
--
通讯作者：
Van Nostrand WE
中科院分区：
文献类型：
--
作者：
Zhu X ;Victor TW ;Ambi A ;Sullivan JK ;Hatfield J ;Xu F ;Miller LM ;Van Nostrand WE
纤维状淀粉样β-蛋白（Aβ）在脑实质斑块和血管中的积累，后一种情况称为脑淀粉样血管病（CAA），是阿尔茨海默病（AD）和相关疾病的标志性病理学。据报道，大脑淀粉样沉积物积累了各种金属，最明显的是铜和锌。在这里，我们表明，在人类AD，铜是优先积累在含淀粉样蛋白的脑血管相比，实质淀粉样蛋白斑块。根据这一观察结果，我们评估了降低Tg 2576小鼠（AD淀粉样病变的转基因模型）中铜水平的影响。将铜螯合剂四硫代钼酸盐（TTM）给予12个月大的Tg 2576小鼠，持续5个月的时间。铜螯合治疗显着降低CAA和实质斑块负荷Tg 2576小鼠。此外，铜螯合降低了实质斑块铜含量，但在该模型中对CAA铜水平没有影响。这些发现表明，铜与CAA沉积和实质淀粉样斑块在人类，但在Tg 2576小鼠较少。TTM仅降低Tg 2576小鼠斑块中的铜水平。降低脑中的铜水平可能有益地降低与AD相关的淀粉样蛋白病理。多模式成像研究显示，Tg 2576小鼠脑血管中的Aβ淀粉样蛋白（绿色）优先结合铜（红色）-铜螯合剂可以减轻这种病理。
Accumulation of fibrillar amyloid β-protein (Aβ) in parenchymal plaques and in blood vessels of the brain, the latter condition known as cerebral amyloid angiopathy (CAA), are hallmark pathologies of Alzheimer’s disease (AD) and related disorders. Cerebral amyloid deposits have been reported to accumulate various metals, most notably copper and zinc. Here we show that, in human AD, copper is preferentially accumulated in amyloid-containing brain blood vessels compared to parenchymal amyloid plaques. In light of this observation, we evaluated the effects of reducing copper levels in Tg2576 mice, a transgenic model of AD amyloid pathologies. The copper chelator, tetrathiomolybdate (TTM), was administered to twelve month old Tg2576 mice for a period of five months. Copper chelation treatment significantly reduced both CAA and parenchymal plaque load in Tg2576 mice. Further, copper chelation reduced parenchymal plaque copper content but had no effect on CAA copper levels in this model. These findings indicate that copper is associated with both CAA deposits and parenchymal amyloid plaques in humans, but less in Tg2576 mice. TTM only reduces copper levels in plaques in Tg2576 mice. Reducing copper levels in the brain may beneficially lower amyloid pathologies associated with AD. Multimodal imaging studies show that Aβ amyloid in brain vessels of Tg2576 mice (green) preferentially binds copper (red) – a pathology that can be reduced with copper chelators.
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影响因子：
4.7
作者：
Jung, SS;Zhang, WB;Van Nostrand, WE
通讯作者：
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